Organic nitrates (nitric acid esters) have proven effective in the therapy of heart diseases. They exert their effectiveness through cardiac support as well as by alleviating the before and after effects of a load on the heart as well as through improvement of the oxygen supply to the heart by dilation of the coronary vessels.
It has been found in recent years that the organic nitrates which have been previously used in heart therapy, such as glycerol trinitrate (GTN), isosorbid-5-mononitrate or isosorbid dinitrate, because of nitrate tolerance, exhibit a clear drop in efficacy in a relatively short time when continuous high dosages are administered to a patient. Numerous experiments indicate that the presence of sulfhydryl (--SH) groups prevents the development of nitrate tolerance and that an existing tolerance can be reduced by the presence of sulfhydryl groups.
The mechanism by which tolerance is developed is presently understood to involve cysteine. According to the present state of knowledge, the pharmacological action of organic nitrate compounds depends on the presence of cysteine. The organic nitrate forms a common precursor with cysteine. When the precursor decomposes, --NO radicals among others which activate soluble guanylate cyclase, the target enzyme of the smooth muscle cells, are released. Subsequent reactions triggered by the formation of cGMP lead to relaxation or dilation of the vessels.
The reactive and short-lived, and so far, only hypothetical intermediate product would have to be a thioester of nitric acid or a thionitrate. Through intra-molecular rearrangement and other subsequent reactions, which have not yet been established, the final formation of a nitroso thiol is postulated, from which nitrogen monoxide or nitrite ions are liberated. On the other hand, the enzyme-dependent degradation with the aid of GSH reductase would not be of significance for the pharmacological action, because it leads exclusively to the formation of nitrite ions. As already stated, the nonenzymatic degradation needs cysteine and thus it can be exhausted in a dose-dependent manner (exhaustion of the --SH group pool) so that over a long term sufficient --NO, which is the actual activator of guanyl cyclase, can no longer be formed so that the clinical effectiveness is reduced.
In the European patent application 89 116 700.9 specifically synthesized compounds are disclosed which contain nitrato fatty acids (nitrato alkanoic acids) and a group from a sulfur-containing amino acid, for example a peptide. The presence of the sulfhydryl group prevents or resists development of nitrate tolerance and/or a reversal of an existing nitrate tolerance.
Compounds which are disclosed, among others, in the European patent application include those with sulfur-containing amino acids like cysteine or methionine in the form of their methyl, ethyl or propyl esters. Finally, the --SH group present in cysteine can be esterified with a lower alkanoic acid having 2 to 8 carbon atoms.
Although these compounds have already demonstrated valuable pharmacological characteristics with respect to the prevention of nitrate tolerance and/or the reversal of an existing tolerance, they have some disadvantages. Thus, they have low melting points, possess low water solubility, and are difficult to purify.
It is one purpose or object of this invention to provide novel organic compounds, particularly compounds which do not have, or have fewer of, the above-mentioned disadvantages.